The objective of this proposal is to provide the applicant with exemplary translational medical research training in the development of diagnostic biomarkers of pediatric disease. To achieve this objective, a training regimen within the scope of inflammatory bowel disease (IBD) had been developed, consisting of research aims and substantial training activities. IBD is an intestinal disorder characterized by chronic inflammation, resulting in a variety of uncomfortable and even dangerous symptoms including diarrhea, weight loss, growth failure, rectal bleeding, abscesses, strictures, or fistulas. IBD comprises two disease types, Crohn's disease (CD) and ulcerative colitis (UC), and is one of the most serious diseases affecting the health of children; the peak diagnosis period for both CD and UC occurs during childhood (1, 2). Due to a lack of conclusive biomarkers, the gold standard for diagnosis and evaluation of IBD is endoscopy/colonoscopy, although this invasive and costly procedure is associated with risks to the patient. Recently, circulating microRNA (miRNA) profiles with diagnostic potential have been described for several conditions, including cancer (3-8). As described in the Preliminary Studies, we have identified a set of circulating miRNAs that are significantly altered in CD. The specific research aims of the proposal are: 1) to identify CD- and UC-specific circulating miRNA profiles for use as diagnostic biomarkers of pediatric IBD and 2) to assess the utility of circulating miRNAs as predictors of outcome and surrogate markers of pediatric IBD. Sera will be obtained from patients presenting for endoscopy/colonoscopy for suspected IBD at the Pediatric IBD Center at the Children's Hospital of Philadelphia. IBD-specific miRNAs will be identified by microarray and confirmed in large, independent sample sets. The diagnostic potential of circulating miRNAs will be compared to current IBD biomarkers using receiver operating characteristic analysis. Longitudinal studies will be performed to determine the utility of circulating miRNAs as surrogate markers and predictors of outcome. In addition to the research aims, a comprehensive training program has been developed; this plan includes coursework in clinical research and seminars and conferences on topics including biomarker discovery, microarray analysis, and professional development. Overall, the proposed training regimen constitutes a balanced introduction to the skills and experience necessary to become a successful independent research investigator and may lead to a dramatic reduction in the need for invasive testing in the diagnosis and clinical management of IBD in children.